title: Morphine mediates a proinflammatory phenotype via μ-opioid receptor-PKCɛ-Akt-ERK1/2 signaling pathway in activated microglial cells.
abstract: Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. Glia has a central role in the development of morphine tolerance. Here, we characterized the receptor-proximal signaling events that link μ-opioid receptors to activation of Akt and ERKs in lipopolysaccharide (LPS)-stimulated murine microglial cells with the aim to define the molecular mechanism contributing to the ability of morphine to increase inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in activated microglial cells. In particular, the role of PKCɛ isoform in μ-opioid-induced inflammatory response in microglia was investigated. The results indicate that morphine increases the LPS-induced expression and activation of PKCɛ and stimulates Akt pathway upstream of ERK1/2 and iNOS. Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6, and of NO via μ-opioid receptor-PKCɛ signaling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Together, these data suggest that the modulation of μ-opioid receptor signaling on microglia through PKCɛ selective inhibition may provide a means to attenuate glial activation and, as a consequence, to treat opioid development of tolerance and dependence.
authors.affiliation: Department of Medical Science, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Debora
authors.initials: D
authors.lastname: Fazzi
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanelli
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004361:Drug Tolerance; D004789:Enzyme Activation; D020868:Gene Silencing; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017450:Receptors, Opioid, mu; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009020:Morphine; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: 4′,6′-diamino-2-phenyl-indole; ANOVA; CNS; DAPI; ELISA; ERK; FBS; IL; LPS; MAPK; Microglia; Morphine; NO; Opioid receptors; PE; PKCɛ; Proinflammatory cytokines; Signaling pathways; TNF; analysis of variance; central nervous system; enzyme-linked immunosorbent assay; extracellular signal-regulated kinase; fetal bovine serum; iNOS; inducible nitric oxide synthase; interleukin; lipopolysaccharide; mitogen-activated protein kinase; nitric oxide; phycoerythrin; siRNA; small interfering RNA; tumor necrosis factor